tbuckley/cabot-search huggingface dataset:
Abstract 1800: Novel NSDHL inhibitor (Compound 9) exerts anti-proliferative and cytotoxic activity in breast cancer cells
Authors: So-Hyun Yoon, Hoe Suk Kim, Moonjou Baek, Seungyeon Ryu, Sangeun Lee, Han-Byoel Lee, Bong-Jin Lee, Wonshik Han
Journal: Cancer Research (2022)

Abstract Background: NAD(P) Dependent Steroid Dehydrogenase-Like (NSDHL) is an enzyme involved in post-squalene cholesterol biosynthesis. We recently suggest new insights into the critical role of the NSDHL involved in breast tumor growth and metastasis and its potential for targeted cancer therapy. Compound 9, which is a novel inhibitor of NSDHL, was kindly provided by Dr. Lee B-J in Seoul National University College of Pharmacy. This study aimed to investigate the anti-cancer potential of Compound 9 in breast cancer. Methods: Therapeutic potential of Compound 9 (10~100 μM) was investigated in several human breast cancer cell lines. Total intracellular cholesterol level was measured using Total Cholesterol Assay Kit. Cell cycle analysis using DNA staining with PI, apoptosis analysis using Annexin V/PI-labeling, and transwell migration assay were performed. The Synergistic anticancer effect of compound-9 and paclitaxel was evaluated by crystal violet assay. Western blot and immunofluorescent staining were assessed for investigating the mechanism by which Compound 9 exerts the anti-cancer effect. Results: Time-dependent intracellular uptake of Compound 9 by breast cancer cells was observed. Compound 9 induced cytotoxic, anti-proliferative, and apoptotic effects and cell cycle arrest (G0/G1), and suppressed migration activity on diverse breast cancer cell lines in a time- and dose-dependent manner. Total intracellular cholesterol level was reduced by Compound 9. Combination with Compound-9 and Paclitaxel led to synergistic cytotoxicity. Compound-9 increased the autophagy-related proteins (P62, LC3II) but decreased the anti-apoptotic proteins (XIAP, BCL2). Conclusion: Our data show that Compound 9 exerts strong anti-proliferative and cytotoxic activity in breast cancer cells, suggesting potential additional utility as an anti-cancer drug. Further studies are necessary to validate the potential anti-cancer effect of Compound-9 in breast tumor mice models. Citation Format: So-Hyun Yoon, Hoe Suk Kim, Moonjou Baek, Seungyeon Ryu, Sangeun Lee, Han-Byoel Lee, Bong-Jin Lee, Wonshik Han. Novel NSDHL inhibitor (Compound 9) exerts anti-proliferative and cytotoxic activity in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1800.
Abstract 5505: ADAM10-targeting CAR-T cells inhibit colon cancer cell growth <i>in vivo</i>
Authors: Elaheh Rohani Rad, Jade Foeng, Dylan McPeak, Timona Tyllis, Caitlin Abbott, Veronika bandara, Silvana Napoli, Batjargal gundsambuu, Simon Barry, Timothy Sadlon, shaun McColl
Journal: Cancer Research (2022)

Abstract Chimeric antigen receptor (CAR) T cell therapy has demonstrated a high degree of efficacy in patients with hematological malignancies such as acute lymphatic leukemia. However, its efficacy in solid tumors remains to be demonstrated. There are a number of issues currently limiting therapeutic treatment of solid tumors with CAR-T cells, none more important than target antigen selection. This is a major challenge in solid tumors due to their heterogenous characteristics and the potential for off-cancer effects. ADAM10, A Disintegrin And Metalloproteinase 10, plays critical roles in a wide range of pathophysiological processes during development and inflammation. These proteolytically active multifunctional proteins act as sheddases by cleaving transmembrane-bound proteins such as growth factors, adhesion molecules and chemokine receptors, which can then contribute to migration and invasion of cancer cells. An active form of ADAM10 that has undergone a conformational change has been identified in several cancer types, particularly colorectal cancer. In this study, a novel CAR was generated based on a previously characterized cancer-specific ADAM10 antibody. ADAM-10-targeting CAR-T cells were manufactured using T cells from the peripheral blood of the healthy donors. The CAR-T cells displayed the naïve and central memory phenotype that has been shown to differentiate and proliferate within tumor microenvironments, with little expression of exhaustion markers. These CAR-T cells were capable of killing several human colorectal tumor cell lines in vitro, assessed in a bioluminescence-based cytotoxicity assay. Furthermore, treatment of NSG mice bearing human LoVo colon cancer cell tumors with ADAM-10-targeting CAR-T cells led to significant inhibition of tumor growth compared with either untransduced control T cells or PBS treatment. Overall, these data suggest that targeting ADAM-10 via CAR-T cell therapy is a promising novel avenue of treatment of colorectal cancer. Citation Format: Elaheh Rohani Rad, Jade Foeng, Dylan McPeak, Timona Tyllis, Caitlin Abbott, Veronika bandara, Silvana Napoli, Batjargal gundsambuu, Simon Barry, Timothy Sadlon, shaun McColl. ADAM10-targeting CAR-T cells inhibit colon cancer cell growth in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5505.
Abstract 2588: M1774, a novel potent and selective ATR inhibitor, shows antitumor effects as monotherapy and in combination
Authors: Astrid Zimmermann, Heike Dahmen, Thomas Grombacher, Ulrich Pehl, Andree Blaukat, Frank T. Zenke
Journal: Cancer Research (2022)

Abstract The protein kinase ataxia telangiectasia- mutated and Rad3-related (ATR) is an important component of the DNA Damage Response (DDR) and a key mediator of the replication stress response (RSR). ATR is recruited to and activated by single-stranded DNA, which commonly forms as a consequence of replication stress (RS). ATR activation and signaling coordinates a multifaceted response to RS, however if left unresolved, replication forks may collapse, form double-strand breaks (DSB), lead to chromosomal rearrangements and eventually cell death. Several chemotherapeutic agents act by increasing RS in tumor cells, by directly damaging the DNA and/or depleting cellular resources required for DNA replication. Increased RS may also result from activation of oncogenes that drive dysregulated replication, a hypoxic environment, or from defects in other repair pathways even in the absence of exogenous DNA damaging insults. Inhibition of ATR activity in cancer cells disables the RSR, potentially enhancing the cytotoxicity of DNA damaging interventions and causing efficacy as monotherapy against tumors with reliance on ATR activity. M1774 is a potent inhibitor of ATR protein kinase with high selectivity towards other protein kinases. A broad range of antiproliferative activities (ranging from ~20 nM to &amp;gt;1 µM) was observed in a cancer cell line panel in vitro. M1774 showed pronounced synergy in combination with several DNA-damaging drugs and inhibitors of the DNA damage response. In vivo efficacy studies confirmed the combination potential suggested from in vitro studies. Pronounced combination benefit with complete tumor growth inhibition/regression was observed in combination with different chemotherapies or targeted DDR pathway inhibitors. Furthermore, M1774 showed pronounced activity as monotherapy in tumor models with gene mutations that result in a reliance on ATR activity. Clinical evaluation is ongoing to investigate M1774 as monotherapy and in combination with niraparib in patients with advanced solid tumors (DDRiver Solid Tumors 301, NCT04170153). Citation Format: Astrid Zimmermann, Heike Dahmen, Thomas Grombacher, Ulrich Pehl, Andree Blaukat, Frank T. Zenke. M1774, a novel potent and selective ATR inhibitor, shows antitumor effects as monotherapy and in combination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2588.
Abstract 5482: Natural product inhibitor of Stat3, G6PD, and TrxR1 functions induces an early oxidative stress and pyroptosis, and a late-stage DNA damage and cell cycle arrest to block tumor growth in human breast cancer models
Authors: Yinsong Zhu, Cody F. Dickinson, Justin Yang, Kyrstin Datanagan, Ning Zhai, Peibin Yue, Francisco Lopez-Tapia, Marcus A. Tius, James Turkson
Journal: Cancer Research (2022)

Abstract Bioactive natural products have led to new drugs or been the inspiration for developing new treatments. Signal transducer and activator of transcription (STAT)3 is a an oncogene that has been implicated in many human cancers. We report that the hirsutinolide natural product, R001, blocks STAT3 DNA-binding activty in vitro. Treatment with R001 of the human triple-negative breast cancer (TNBC) cells, MDA-MB-231 and MDA-MB-468 led to the concurrent inhibition of constitutively-active STAT3 and the expression and activities of glucose-6-phosphate 1-dehydrogenase (G6PD) and thioredoxin reductase (TrxR)1, early suppression of glutathione (GSH), and the induction of reactive oxygen species (ROS), which peaked at 6-24 h post R001-treatment. In the short term, R001-treated TNBC cells showed evidence of pyroptotic cell death. Prolonged treatment of TNBC cells with R001 led to DNA damage and G2/M-phase cell cycle arrest, which are late-stage responses that were preceded by the suppression of ATM-Chk2-Cdc25c pathway, and the induction of p21 and γH2AX phosphorylation by the natural product. Accordingly, R001 suppressed the viable cell numbers, colony formation, growth in 3D-matrigel, and the migration of MDA-MB-231 and MDA-MB-468 cells in vitro. The oral administration of R001 at 5 mg/kg signficantly inhibited growth of human MDA-MB-468 xenografts in mice. Results together show that R001 inhibits STAT3, G6PD and TrxR1 functions that lead to early oxidative stress and pyroptosis and late-stage DNA damage and cell cycle arrest, which collectively cause tumor cell death and tumor growth inhibition in human TNBC models. Citation Format: Yinsong Zhu, Cody F. Dickinson, Justin Yang, Kyrstin Datanagan, Ning Zhai, Peibin Yue, Francisco Lopez-Tapia, Marcus A. Tius, James Turkson. Natural product inhibitor of Stat3, G6PD, and TrxR1 functions induces an early oxidative stress and pyroptosis, and a late-stage DNA damage and cell cycle arrest to block tumor growth in human breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5482.
Abstract 2611: The NEDD8 pathway as a therapeutic target in HER2-amplified colorectal cancer
Authors: Federica Invrea, Alessandro Carugo, Sabrina Arena, Alberto Bardelli, Giulio F. Draetta, Enzo Medico
Journal: Cancer Research (2022)

Abstract Colorectal cancer (CRC) is a heterogeneous disease with a wide spectrum of clinical outcomes, from indolent resectable disease to aggressive-metastatic cases. Primary and acquired resistance limits the efficacy of available treatments, and the identification of effective drug combinations is needed to further improve patients' outcomes. We previously found that the NEDD8-activating enzyme inhibitor pevonedistat induced tumor stabilization in preclinical models of poorly differentiated, clinically aggressive CRC resistant to available therapies. To identify drugs that can be effectively combined with pevonedistat, we performed a "drop-out" loss-of-function synthetic lethality screening with an shRNA library covering 200 drug-target genes in four different CRC cell lines. Multiple screening hits were found to be involved in the EGFR signaling pathway, suggesting that, rather than inhibition of a specific gene, interference with the EGFR pathway at any level could be effectively leveraged for combination therapies based on pevonedistat. Exploiting both BRAF-mutant and RAS/RAF wild-type CRC models, we validated the therapeutic relevance of our findings by showing that combined blockade of NEDD8 and EGFR pathways led to increased growth arrest and apoptosis both in vitro and in vivo. Pathway modulation analysis showed that compensatory feedback loops induced by single treatments were blunted by the combinations. Our results suggested possible therapeutic opportunities in specific CRC clinical settings. We further focused on HER2 amplified CRC cells and we observed cooperation between pevonedistat and HER2/EGFR blockade by the trastuzumab + lapatinib combination -the current standard treatment for HER2-amplified CRC. In addition, to confirm cooperation in reducing colony formation in vitro, we explored the effect of pevonedistat on long-term persisters, i.e., cell surviving to several weeks of HER2/EGFR blockade. Interestingly, we observed a marked decrease of cell colonies when pevonedistat was added to persisters survived to three weeks of trastuzumab + lapatinib treatment. These results unveil the possibility of testing in vivo the addition of pevonedistat subsequently to tumor stabilization or reduction by HER2/EGFR blockade, to promote further tumor regression. Citation Format: Federica Invrea, Alessandro Carugo, Sabrina Arena, Alberto Bardelli, Giulio F. Draetta, Enzo Medico. The NEDD8 pathway as a therapeutic target in HER2-amplified colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2611.
Abstract 439: Physical activity among male cancer survivors during the COVID-19 pandemic
Authors: Colleen B. McGrath, Alaina H. Shreves, Konrad Stopsack, Lilian Cheung, Ann Fisher, Sarah Markt, Lorelei A. Mucci
Journal: Cancer Research (2022)

Abstract Introduction: The COVID-19 pandemic has greatly disrupted the lives of cancer survivors. Beyond being at increased risk for COVID-19 infection and severe complications, cancer survivors may be at higher risk of other consequential health outcomes compared to those without a history of cancer. Engagement in physical activity has been shown to positively affect cancer survivorship outcomes, and as such, it is important to assess physical activity habits during the pandemic of cancer survivors. Aim: To investigate the individual-level physical activity among male cancer survivors during the COVID-19 pandemic and compare to men without cancer. Methods: Participants of the Health Professionals Follow-up Study, enrolled since 1986, were asked to self-report health behaviors during the pandemic on three web-based questionnaires administered during the COVID-19 pandemic (baseline COVID: October 2020, first follow-up: January 2021, second follow-up: April 2021). Physical activity measures were analyzed descriptively between cancer survivors and individuals without a history of cancer. Outcomes were recoded dichotomously to reflect either: healthful (i.e., higher engagement since pandemic) vs unchanged/unhealthful behavior or high vs low engagement in an activity. Logistic regression models were employed to assess association with cancer survivor status and were adjusted for covariates such as age, race, pre-pandemic BMI, pre-pandemic physical activity, and other health information, as appropriate. Results: Of 4,416 men who completed the baseline COVID-19 questionnaire, 962 were cancer survivors (after excluding those with non-melanoma skin cancer). Of all eligible men (median age: 78 years) reporting on physical activity, over 50% walked for at least 2-3 hours per week, over 10% used a stationary bike for at least 1 hour per week, 14% engaged in yoga for at least 1 hour per week, and nearly 20% engaged in vigorous activity for at least 1 hour per week. Further, 42% engaged in high (1+ times per day) levels of mindfulness and 24% engaged in high (1+ times per day) levels of yoga. Engagement in vigorous physical activity was significantly lower among cancer survivors compared to individuals without a history of cancer (Chi-square p = 0.01). Conclusion: Our findings suggest older men had high engagement in physical activity during the COVID-19 pandemic, with vigorous physical activity engagement significantly lower in cancer survivors. Citation Format: Colleen B. McGrath, Alaina H. Shreves, Konrad Stopsack, Lilian Cheung, Ann Fisher, Sarah Markt, Lorelei A. Mucci. Physical activity among male cancer survivors during the COVID-19 pandemic [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 439.
Abstract 1698: Copy number diversity within and across tumor types
Authors: Toby Baker, Stefan Dentro, Paul Spellman, Maxime Tarabichi, Peter Van Loo
Journal: Cancer Research (2022)

Abstract Introduction Cancers commonly accrue copy number gains and losses during their development. An improved understanding of their contribution to tumorigenesis can be gained by studying their distribution and evolution within and across tumor types. Materials and Methods We analyzed copy number profiles of 16,765 tumours from the Hartwig Medical Foundation, Pan-Cancer Analysis of Whole Genomes (PCAWG) and The Cancer Genome Atlas (TCGA) cohorts. We used a novel timing method, ComplexTiming, to time the occurrence of copy number gains, and a permutation-based approach to assess the distribution of copy number events relative to a null distribution. Results Complex copy number states in cancers that have undergone a whole-genome duplication (WGD) are commonly assumed to develop through a most parsimonious route, where the series of events leading to the complex copy number state requiring the least number of steps, is proposed to be the most likely one. Our newly developed ComplexTiming approach allows unique insights into the actual routes that led to these complex copy number states. In our large pan-cancer cohort, we found that the most parsimonious set of events does not occur in approximately 40% of cases. Additional gains more frequently occurred after WGD than before, reflecting a previously observed increase in instability. In squamous cell lung cancer, gains of 3q were frequently found before WGD. Additionally, 5q and 1q were significantly more likely to be gained before WGD in colorectal and melanoma metastases, respectively. Evaluating the distribution of copy number events, we found that the majority of copy number events are distributed across tumors consistent with a permutation model that assigns copy number events randomly. However, interestingly, in the majority of cancer types, we found copy number events that occurred more often than expected in individual tumors with low numbers of events, such as loss of chromosome 9 in bladder cancer, loss of 20p in colorectal adenocarcinomas, and gain of 1q in breast adenocarcinomas. These results suggest that the high-frequency of these specific copy number events is due to selection, while other copy number changes may occur neutrally due to innate chromosome instability. Conclusion The landscape of copy number gains in tumors is diverse. By analyzing the timing of these events as well as their distribution, we identify a subset of frequent copy number changes in different cancer types that are likely under selection. Citation Format: Toby Baker, Stefan Dentro, Paul Spellman, Maxime Tarabichi, Peter Van Loo. Copy number diversity within and across tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1698.
Abstract 2922: Targeting triple negative breast cancer with a VHL recruiting EZH2 protein degrader
Authors: Brandon Dale, Chris Anderson, Kwang-su Park, H. Ümit Kaniskan, Xufen Yu, Jian Jin
Journal: Cancer Research (2022)

Abstract EZH2 (enhancer of zeste homolog 2) is the main catalytic subunit of the polycomb repressive complex 2 (PRC2) that catalyzes methylation of histone H3K27. EZH2 is overexpressed in a broad spectrum of cancers including prostate, myeloma and lymphoma, and high expression correlates with poor prognosis. However, EZH2 inhibitors, which do not affect EZH2 protein levels, are ineffective at inhibiting growth of TNBC and other breast cancer cell lines with EZH2 overexpression even though they effectively inhibit the catalytic activity of EZH2/PRC2. It has also been shown that overexpression of EZH2 is a major driver for breast cancer development and progression, and knockdown of EZH2 inhibits proliferation of TNBC and other breast cancer cells. These results together suggest that EZH2 overexpression, but not the methyltransferase activity of EZH2, is critical for driving breast cancer progression. Bivalent inhibitor technologies such as PROTACs (proteolysis targeting chimeras) and hydrophobic tagging have been successfully applied to selective degradation of multiple protein targets. CRBN-recruiting (E7) and VHL-recruiting EZH2 (YM281) EZH2 targeting PROTACs have been reported, but do not show potent efficacy in targeting TNBC. Here, we characterize MS8815, a VHL-recruiting EZH2 degrader, that we created. MS8815 displayed nanomolar efficacy at EZH2 degradation and potent in vitro effects on TNBC cell lines, no off-target interactions and utilized the canonical PROTAC mechanism of action. Based on these promising preliminary results, we report MS8815 as the best-in-class EZH2 PROTAC degrader that is able to efficiently degrade EZH2 and kill TNBC cells. Citation Format: Brandon Dale, Chris Anderson, Kwang-su Park, H. Ümit Kaniskan, Xufen Yu, Jian Jin. Targeting triple negative breast cancer with a VHL recruiting EZH2 protein degrader [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2922.
Abstract 3726: Functional genomic dissection of <i>PIK3CA</i> hotspot mutations using a multi-lineage isogenic breast cell model
Authors: Adam X. Miranda, Emily Hodges, Ben Ho Park
Journal: Cancer Research (2022)

Abstract PIK3CA is the most commonly mutated gene in breast cancer, and in breast cancer there are two hotspot mutations that represent an outsized proportion of PIK3CA mutations. Previous research suggests that there are distinct prognostic and cell signaling differences induced by these mutational isoforms, however there is currently only one targeted treatment approved for PIK3CA mutant breast cancer. The goal of our research is to leverage a comprehensive multi-lineage isogenic breast cell line model to further interrogate the unique effects of these PIK3CA mutations on breast cells using assays to assess gene expression and chromatin state. Insights gained from these assays shed light on disrupted pathways that may prove to be new targets for PIK3CA mutation-specific treatment of breast cancer. Citation Format: Adam X. Miranda, Emily Hodges, Ben Ho Park. Functional genomic dissection of PIK3CA hotspot mutations using a multi-lineage isogenic breast cell model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3726.